DESCRIPTION: Applicant's Abstract HIV-associated dementia complex (HADC), a common illness in AIDS, is one of the most common causes of dementia in adults under the age of 50. Although drug abuse is a recognized factor in the spread of HIV infection, it is unclear what effect commonly abused drugs might have on the progression of HIV infection and, in particular, HADC. Clinical studies suggest that cocaine abuse might influence the development and/or course of HADC, but direct evidence is lacking. In addition to its effects on brain function and pathology (effects which may potentiate those seen in HADC), cocaine has profound systemic immunomodulatory consequences which may compound the immune effects of retroviral infection. Recent evidence that cocaine influences retroviral infection in a murine model and increases the production of HIV in peripheral blood mononuclear cell cultures supports this possibility. The proposed research utilizes a model of HIV encephalitis in SCID mice to investigate the effects of cocaine on the neuropathology and behavioral abnormalities associated with HIV infection. SCID mice, inoculated intracerebrally with human peripheral blood mononuclear cells and HIV, develop similar histopathology to humans with HIV encephalitis. Importantly, with respect to the proposed studies, SCID mice with HIV encephalitis also exhibit behavioral abnormalities. We hypothesize that chronic cocaine exposure will increase the severity of pathological and behavioral abnormalities associated with HIV infection. This hypothesis will be tested with specific aims to determine if cocaine exposure: (1) alters the amount of HIV present in the brains of mice with HIV encephalitis; (2) contributes to the severity of pathology associated with HIV encephalitis as indexed by amounts of (a) astrogliosis and (b) neuronal apoptosis; (3) modulates cytokine activity during HIV encephalitis; (4) enhances the motor slowing and cognitive dysfunction associated with HIV encephalitis as indexed by performance on motor activity tests and on a spatial learning task (Morris Maze). The proposed experiments will contribute toward understanding to what extent abused drugs might alter the course of HADC as well as provide possible mechanisms for such alterations.